Preserved heart function after left ventricular pressure overload in adult mice subjected to neonatal cardiac hypoplasia.

Intrauterine growth restriction in animal models reduces heart size and cardiomyocyte number at birth. Such incomplete cardiomyocyte endowment is believed to increase susceptibility toward cardiovascular disease in adulthood, a phenomenon referred to as developmental programming. We have previously described a mouse model of impaired myocardial development leading to a 25% reduction of cardiomyocyte number in neonates. This study investigated the response of these hypoplastic hearts to pressure overload in adulthood, applied by abdominal aortic constriction (AAC). Echocardiography revealed a similar hypertrophic response in hypoplastic hearts compared with controls over the first 2 weeks. Subsequently, control mice develop mild left ventricular (LV) dilation, wall thinning and contractile dysfunction 4 weeks after AAC, whereas hypoplastic hearts fully maintain LV dimensions, wall thickness and contractility. At the cellular level, controls exhibit increased cardiomyocyte cross-sectional area after 4 weeks pressure overload compared with sham operated animals, but this hypertrophic response is markedly attenuated in hypoplastic hearts. AAC mediated induction of fibrosis, apoptosis or cell cycle activity was not different between groups. Expression of fetal genes, indicative of pathological conditions, was similar in hypoplastic and control hearts after AAC. Among various signaling pathways involved in cardiac hypertrophy, pressure overload induces p38 MAP-kinase activity in hypoplastic hearts but not controls compared with the respective sham operated animals. In summary, based on the mouse model used in this study, our data indicates that adult hearts after neonatal cardiac hypoplasia show an altered growth response to pressure overload, eventually resulting in better functional outcome compared with controls.

5-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-7-phenyl-2,3,6,7-tetrahydro-1,4-thiazepines as compounds with high affinity at the benzodiazepine binding site on GABA(A) receptors.

A series of thiazepines has been studied as new ligands for the benzodiazepine binding site of the GABAA receptor. Compounds with high affinity and weak selectivity regarding alpha beta3gamma2, alpha2beta3gamma2, alpha3beta3gamma2, and alpha5beta3gamma2 subtypes were found. The pharmacophore is discussed based on experimental and theoretical results. The thiazepine sulfur atom was found to be able to act as hydrogen bond acceptor.

Renal function and urine drainage after conservative or operative treatment of primary (obstructive) megaureter in infants and children.

UNLABELLED: We examined renal function and urinary drainage of children with primary megaureter (PMU) in dependence on conservative or operative treatment. MATERIAL AND METHODS: The retrospective analysis covering the years 1994 to 2000 comprised children at an age of 0-7 years with 35 PMU. Sonography, dynamic MAG3 renography as well as endogenic creatinine clearance (GFR) were used to assess drainage and the renal function. Temporary urinary diversion was established in fourteen patients of both groups. In 14 children with 16 PMU a ureteroneocystostomy (UNC) was performed. The average observation period was 30 months (11-108). RESULTS: The children of the UNC group differed from the non-neoimplanted group in the age at diagnosis (10.5 vs. < 1 months), higher degrees of hydronephrosis on average, a more distinct dilatation of the ureter as well as renographically significant obstruction. Children of the non-UNC group, including four children with a type B drainage curve (O'Reilly), had an unimpaired differential renal function or improved during the observation period (initially 51% vs. 50.5% at the end). In neoimplantation group the differential function improved from 32.5% to 38.5% (p < 0.05) and obstruction resolved with one exception. CONCLUSION: Given a higher-grade PMU with a reduced function of the kidneys and a significant impaired drainage pattern and/or symptoms, neoimplantation without temporary diversion has proved to be an efficient renoprotective method. Furthermore, data clearly justify a conservative approach without urinary diversion in infants with large asymptomatic PMU.

[Arthroscopic joint debridement for gonarthrosis: influence of degree of chondral damage and muscle weakness on results]. / Arthroskopisches Gelenkdebridement bei aktivierter Varusgonarthrose. Der Einfluss der Schwere des Knorpelschadens und des muskulären Defizits auf das Ergebnis.

AIM: Purpose of this study was to investigate the correlation between subjective patient discomfort, chondral damage and muscular weakness in cases of gonarthrosis (OA). METHODS: In 22 patients suffering from OA who underwent arthroscopy, the complaints were scored by the Lysholm score. Chondral damage was determined by a special "chondral score". The maximum peak torque was measured pre- and postoperatively (isokinetic test, Cybex 6000 dynamometer). RESULTS: Joint debridement and subsequent postoperative aggressive rehabilitation produced a significant increase in the Lysholm score (from 45.7 to 77.5 points). Subjective complaints correlated significantly with the degree of chondral damage. After treatment, the strength of the extensor muscles increased significantly. The strength of the flexor muscles strength also increased tendentially. However, there was a deficit in muscular strength in comparison to the contralateral leg in all cases. The subjective complaints correlated with the loss of muscle strength at slow angular velocities. CONCLUSIONS: The patients" evaluation with the Lysholm score in combination with an arthroscopic chondral score and the measurement of the isokinetic muscle strength is a suitable method to obtain information about the chances of success for arthroscopic joint debridement in patients suffering from OA. Arthroscopic treatment is an appropriate measure for a short-term reduction of subjective complaints in OA. But it is also useful to reduce muscular deficits.

[Identity and physicochemical properties of 1-(4-chlorophenyl)-4-morpholino-imidazolin-2-one, AWD 131-138]. / Identität und physikochemische Eigenschaften von 1-(4-Chlorphenyl)-4-morpholino-imidazolin-2-on, AWD 131-138.

The structure of the anticonvulsant 1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazolin-2-one (Code: AWD 131-138, CAS-No.: 188116-07-6) was proved by IR, UV, 1H NMR, 13C NMR and mass spectra. AWD 131-138 is practically insoluble in a neutral aqueous medium at 20 degrees C (S approximately 0.08 g/l). The solubility of the substance in 0.1 N HCl is about 2.7 g/l. In DMF, AWD 131-138 is sparingly soluble (S approximately 28.5 g/l). The pKa-value is about 2.5. The partition coefficients P = COctanol/Cwater at 37 degrees C range from 0.7 at pH approximately 1 to about 20 at pH > or = 6.

Effects of the immunomodulator linomide on macrophage migration and myelin phagocytic activity in peripheral nerve trauma: an experimental study.

Wallerian degeneration after peripheral nerve transection leads to the phagocytosis of degenerated myelin and axon components by macrophages. These phagocytes are recruited from the systemic circulation and Wallerian degeneration may therefore be used as a model for myelin removal by hematogenous macrophages, a feature that is also a hallmark of demyelinating diseases of the central and peripheral nervous system. The immunomodulator linomide has been shown to be effective in the treatment of experimental demyelinating diseases although the exact mode of its action is not yet defined. The present study investigated the effect of linomide on monocyte invasion and myelin phagocytosis after sciatic nerve transection. Linomide had a dual effect in Wallerian degeneration. Monocyte migration from the circulation to the damaged nervous system was significantly reduced. Additionally, the myelin phagocytic capacity of macrophages was impaired, finally resulting in a significant delay in the removal of myelin. The present experiments may provide an explanation for the effects of linomide during the course of demyelinating diseases of the nervous system.

Metabolism of retigabine (D-23129), a novel anticonvulsant.

Retigabine (D-23129, N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester) is a potent anticonvulsant in a variety of animal models. Rats metabolized [14C]retigabine mainly through glucuronidation and acetylation reactions. Glucuronides were detected in incubates with liver microsomes or slices, in plasma, and in bile and feces but were absent in urine (0-24 h) that contained about 2% of the dose as retigabine and approximately 29% of the dose in > 20 metabolites, which are derived mainly from acetylation reactions. About 67% of the radioactivity was excreted into feces, approximately 10% of the dose as glucuronide. The metabolite pattern in the urine (0-24 h) of dogs was comparatively simple in that retigabine (13%), retigabine-N-glucuronide (5%), and retigabine-N-glucoside (1%) were present. In the same 24-h interval, about 39% of unchanged retigabine was excreted into feces. Plasma profiling and spectroscopic analysis (liquid chromatography with tandem mass spectrometry NMR) of two isolated urinary metabolites obtained after single oral dosing of 600 mg retigabine in healthy volunteers indicated that both acetylation and glucuronidation are major metabolic pathways of retigabine in humans. We found that in vitro assays with liver slices from rat and humans reveal the major circulating metabolites in vivo.

[A method for the preparation of macroscopic serial sections of human brains at defined levels in the topographic aspects of computized axial tomography]. / Eine Methode zur Herstellung makroskopischer Serienschnitte von menschlichen Gehirnen in definierten Ebenen unter dem topographischen Aspekt der axialen Computertomographie.

The authors describe a method to prepare macroscopic serial sections of human brain in accord with the computer tomography reference lines. Whole brains were orientated after formalin fixation in a special perspex box, embedded in polyurethane filling foam (SYSpur) and cut into 5 or 3 mm thick sections.